Heart failure affects more than 5 million Americans, and strikes over 500,000 new patients each year. Due in the majority of instances to dilated or ischemic cardiomyopathies, heart failure is a classic "complex disease", i.e. it is multi-factorial and has both environmental and genetic components. Despite estimates that genetics contributes ~30% to overall heart failure pathogenesis, clinical management of sporadic heart failure does not currently incorporate genetic information because the genetic factors that modify heart failure risk, prognosis, and response to therapies are largely unknown. Several recently completed or ongoing large-scale microarray analyses of heart failure have identified, replicated, and validated genetic polymorphisms (SNPs) associated with ischemic or non-ischemic cardiomyopathy. We hypothesize that these SNPs are markers for non- synonymous gene variants that predispose to heart failure, and will therefore be useful to risk-stratify and personalize management of individuals in at-risk populations. Accordingly, we have formed the WUMAP consortium from Washington University, Mid America Heart Institute (University of Missouri, Kansas City), and University of Pennsylvania to directly examine genetic risks, genetic modifiers, and pharmacogenomic interactions. Collectively, we have existing heart disease cohorts totaling over 7,700 subjects that have undergone or are currently undergoing microarray analyses to identify candidate gene-disease associations. Based on these results, and to prepare for Stage 2 clinical trials evaluating whether genetic factors improve upon clinical profiling in disease surveillance and management, we will: Aim 1, perform deep resequencing of associated genes/loci in our existing study populations to identify likely causal variants, and select for prospective study those that validate and replicate between independent cohorts. And Aim 2, develop effective collaborations across the WUMAP network by harmonizing our existing research databases, establish centralized Biomarker and Genetics Laboratories, create a web-based WUMAP Data Coordinating Center, Echocardiography and Statistical Genomics Cores, and create a Data Safety Monitoring Board. Stage 1 will thus position us literally to "turn the key" and carry forward multicenter clinical interventional trials to prospectively assess the safety and efficacy of personal genetic information, as an adjunct to clinical data, in heart failure management. PUBLIC HEALTH RELEVANCE: There is a need for prospective evaluations of genetic testing to determine if addition of genetic information to traditional clinical data can improve diagnosis, prognostication, or management of systolic heart failure. The promise of large-scale genomics studies is that unsuspected gene-disease associations will identify markers of disease risk, and will provide novel insight into disease pathogenesis leading to innovative treatment strategies. An intriguing possibility is that genetic data will lead to application of existing therapeutics to new diseases, thus "fast-tracking" the time from discovery to new therapeutics.